Course of psychotic symptoms, depression and global functioning in persons at clinical high risk of psychosis: Results of a longitudinal observation study over three years focusing on both converters and non-converters

AbstractSchizophrenia is characterised by cognitive impairments that are already present during early stages, including in the clinical high-risk for psychosis (CHR-P) state and first-episode psychosis (FEP). Moreover, data suggest the presence of distinct cognitive subtypes during early-stage psychosis, with evidence for spared vs. impaired cognitive profiles that may be differentially associated with symptomatic and functional outcomes. Using cluster analysis, we sought to determine whether cognitive subgroups were associated with clinical and functional outcomes in CHR-P individuals. Data were available for 146 CHR-P participants of whom 122 completed a 6- and/or 12-month follow-up; 15 FEP participants; 47 participants not fulfilling CHR-P criteria (CHR-Ns); and 53 healthy controls (HCs). We performed hierarchical cluster analysis on principal components derived from neurocognitive and social cognitive measures. Within the CHR-P group, clusters were compared on clinical and functional variables and examined for associations with global functioning, persistent attenuated psychotic symptoms and transition to psychosis. Two discrete cognitive subgroups emerged across all participants: 45.9% of CHR-P individuals were cognitively impaired compared to 93.3% of FEP, 29.8% of CHR-N and 30.2% of HC participants. Cognitively impaired CHR-P participants also had significantly poorer functioning at baseline and follow-up than their cognitively spared counterparts. Specifically, cluster membership predicted functional but not clinical outcome. Our findings support the existence of distinct cognitive subgroups in CHR-P individuals that are associated with functional outcomes, with implications for early intervention and the understanding of underlying developmental processes.

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What Causes the Onset of Psychosis in Individuals at Clinical High Risk? A Meta-analysis of Risk and Protective Factors

Schizophrenia Bulletin ◽

10.1093/schbul/sbz039 ◽

2019 ◽

Vol 46 (1) ◽

pp. 110-120 ◽

Cited By ~ 23

Author(s):

Dominic Oliver ◽

Thomas J Reilly ◽

Ottone Baccaredda Boy ◽

Natalia Petros ◽

Cathy Davies ◽

...

Keyword(s):

High Risk ◽

Protective Factors ◽

Meta Analysis ◽

Risk And Protective Factors ◽

Convincing Evidence ◽

Psychotic Symptoms ◽

Clinical High Risk ◽

Global Functioning ◽

Suggestive Evidence ◽

Class Iv

AbstractTwenty percent of individuals at clinical high risk for psychosis (CHR-P) develop the disorder within 2 years. Extensive research has explored the factors that differentiate those who develop psychosis and those who do not, but the results are conflicting.The current systematic review and meta-analysis comprehensively addresses the consistency and magnitude of evidence for non-purely genetic risk and protective factors associated with the risk of developing psychosis in CHR-P individuals. Random effects meta-analyses, standardized mean difference (SMD) and odds ratio (OR) were used, in combination with an established stratification of evidence that assesses the association of each factor and the onset of psychotic disorders (from class I, convincing evidence to class IV weak evidence), while controlling for several types of biases.A total of 128 original controlled studies relating to 26 factors were retrieved. No factors showed class I-convincing evidence. Two further factors were associated with class II-highly suggestive evidence: attenuated positive psychotic symptoms (SMD = 0.348, 95% CI: 0.280, 0.415) and global functioning (SMD = −0.291, 95% CI: −0.370, −0.211). There was class III-suggestive evidence for negative psychotic symptoms (SMD = 0.393, 95% CI: 0.317, 0.469). There was either class IV-weak or no evidence for all other factors.Our findings suggest that despite the large number of putative risk factors investigated in the literature, only attenuated positive psychotic symptoms, global functioning, and negative psychotic symptoms show suggestive evidence or greater for association with transition to psychosis. The current findings may inform the refinement of clinical prediction models and precision medicine in this field.

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Faculty Opinions recommendation of Efficacy and Acceptability of Interventions for Attenuated Positive Psychotic Symptoms in Individuals at Clinical High Risk of Psychosis: A Network Meta-Analysis.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.733520235.793567538 ◽

2019 ◽

Author(s):

Vijay Mittal

Keyword(s):

High Risk ◽

Meta Analysis ◽

Psychotic Symptoms ◽

Clinical High Risk

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Interactions between hippocampal activity and striatal dopamine in people at clinical high risk for psychosis: relationship to adverse outcomes

Neuropsychopharmacology ◽

10.1038/s41386-021-01019-0 ◽

2021 ◽

Author(s):

Gemma Modinos ◽

Anja Richter ◽

Alice Egerton ◽

Ilaria Bonoldi ◽

Matilda Azis ◽

...

Keyword(s):

High Risk ◽

Functional Outcomes ◽

Mental States ◽

Adverse Outcomes ◽

Striatal Dopamine ◽

Psychotic Symptoms ◽

Dopamine Synthesis ◽

Clinical High Risk ◽

Hippocampal Activity ◽

The Relationship

AbstractPreclinical models propose that increased hippocampal activity drives subcortical dopaminergic dysfunction and leads to psychosis-like symptoms and behaviors. Here, we used multimodal neuroimaging to examine the relationship between hippocampal regional cerebral blood flow (rCBF) and striatal dopamine synthesis capacity in people at clinical high risk (CHR) for psychosis and investigated its association with subsequent clinical and functional outcomes. Ninety-five participants (67 CHR and 28 healthy controls) underwent arterial spin labeling MRI and 18F-DOPA PET imaging at baseline. CHR participants were followed up for a median of 15 months to determine functional outcomes with the global assessment of function (GAF) scale and clinical outcomes using the comprehensive assessment of at-risk mental states (CAARMS). CHR participants with poor functional outcomes (follow-up GAF < 65, n = 25) showed higher rCBF in the right hippocampus compared to CHRs with good functional outcomes (GAF ≥ 65, n = 25) (pfwe = 0.026). The relationship between rCBF in this right hippocampal region and striatal dopamine synthesis capacity was also significantly different between groups (pfwe = 0.035); the association was negative in CHR with poor outcomes (pfwe = 0.012), but non-significant in CHR with good outcomes. Furthermore, the correlation between right hippocampal rCBF and striatal dopamine function predicted a longitudinal increase in the severity of positive psychotic symptoms within the total CHR group (p = 0.041). There were no differences in rCBF, dopamine, or their associations in the total CHR group relative to controls. These findings indicate that altered interactions between the hippocampus and the subcortical dopamine system are implicated in the pathophysiology of adverse outcomes in the CHR state.

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What makes the psychosis ‘clinical high risk’ state risky: psychosis itself or the co-presence of a non-psychotic disorder?

Epidemiology and Psychiatric Sciences ◽

10.1017/s204579602100041x ◽

2021 ◽

Vol 30 ◽

Author(s):

Laila Hasmi ◽

Lotta-Katrin Pries ◽

Margreet ten Have ◽

Ron de Graaf ◽

Saskia van Dorsselaer ◽

...

Keyword(s):

High Risk ◽

Drug Use ◽

Psychotic Disorder ◽

Positive Family History ◽

Mental Health Service Use ◽

Psychotic Symptoms ◽

Polygenic Risk Score ◽

Clinical High Risk ◽

Drug Use Disorders ◽

Per Se

Abstract Aims Although attenuated psychotic symptoms in the psychosis clinical high-risk state (CHR-P) almost always occur in the context of a non-psychotic disorder (NPD), NPD is considered an undesired ‘comorbidity’ epiphenomenon rather than an integral part of CHR-P itself. Prospective work, however, indicates that much more of the clinical psychosis incidence is attributable to prior mood and drug use disorders than to psychosis clinical high-risk states per se. In order to examine this conundrum, we analysed to what degree the ‘risk’ in CHR-P is indexed by co-present NPD rather than attenuated psychosis per se. Methods We examined the incidence of early psychotic experiences (PE) with and without NPD (mood disorders, anxiety disorders, alcohol/drug use disorders), in a prospective general population cohort (n = 6123 at risk of incident PE at baseline). Four interview waves were conducted between 2007 and 2018 (NEMESIS-2). The incidence of PE, alone (PE-only) or with NPD (PE + NPD) was calculated, as were differential associations with schizophrenia polygenic risk score (PRS-Sz), environmental, demographical, clinical and cognitive factors. Results The incidence of PE + NPD (0.37%) was lower than the incidence of PE-only (1.04%), representing around a third of the total yearly incidence of PE. Incident PE + NPD was, in comparison with PE-only, differentially characterised by poor functioning, environmental risks, PRS-Sz, positive family history, prescription of antipsychotic medication and (mental) health service use. Conclusions The risk in ‘clinical high risk’ states is mediated not by attenuated psychosis per se but specifically the combination of attenuated psychosis and NPD. CHR-P/APS research should be reconceptualised from a focus on attenuated psychotic symptoms with exclusion of non-psychotic DSM-disorders, as the ‘pure' representation of a supposedly homotypic psychosis risk state, towards a focus on poor-outcome NPDs, characterised by a degree of psychosis admixture, on the pathway to psychotic disorder outcomes.

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Two-year follow-up of a Chinese sample at clinical high risk for psychosis: timeline of symptoms, help-seeking and conversion

Epidemiology and Psychiatric Sciences ◽

10.1017/s2045796016000184 ◽

2016 ◽

Vol 26 (3) ◽

pp. 287-298 ◽

Cited By ~ 21

Author(s):

T. H. Zhang ◽

H. J. Li ◽

K. A. Woodberry ◽

L. H. Xu ◽

Y. Y. Tang ◽

...

Keyword(s):

High Risk ◽

Symptom Onset ◽

Help Seeking ◽

Cox Regression ◽

Clinical Population ◽

Psychotic Symptoms ◽

Clinical High Risk ◽

Chinese Sample ◽

Over Time

Background.Chinese psychiatrists have gradually started to focus on those who are deemed to be at ‘clinical high-risk (CHR)’ for psychosis; however, it is still unknown how often those individuals identified as CHR from a different country background than previously studied would transition to psychosis. The objectives of this study are to examine baseline characteristics and the timing of symptom onset, help-seeking, or transition to psychosis over a 2-year period in China.Method.The presence of CHR was determined with the Structured Interview for Prodromal Syndromes (SIPS) at the participants' first visit to the mental health services. A total of 86 (of 117) CHR participants completed the clinical follow-up of at least 2 years (73.5%). Conversion was determined using the criteria of presence of psychotic symptoms (in SIPS). Analyses examined baseline demographic and clinical predictors of psychosis and trajectory of symptoms over time. Survival analysis (Kaplan–Meier) methods along with Log-rank tests were performed to illustrate the relationship of baseline data to either conversion or non-conversion over time. Cox regression was performed to identify baseline predictors of conversion by the 2-year follow-up.Results.In total 25 (29.1%) of 86 completers transitioned to a psychotic disorder over the course of follow-up. Among the CHR sample, the mean time between attenuated symptom onset and professional help-seeking was about 4 months on average, and converters developed fully psychotic symptoms about 12 months after symptom onset. Compared with those CHR participants whose risk syndromes remitted over the course of the study, converters had significantly longer delays (p = 0.029) for their first visit to a professional in search of help. At baseline assessment, the conversion subgroup was younger, had poorer functioning, higher total SIPS positive symptom scores, longer duration of untreated prodromal symptoms, and were more often given psychosis-related diagnoses and subsequently prescribed antipsychotics in the clinic.Conclusions.Chinese CHR identified primarily by a novel clinical screening approach had a 2-year transition rate comparable with those of specialised help-seeking samples world-wide. Early clinical intervention with this functionally deteriorating clinical population who are suffering from attenuated psychotic symptoms, is a next step in applying the CHR construct in China.

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Efficacy and Acceptability of Interventions for Attenuated Positive Psychotic Symptoms in Individuals at Clinical High Risk of Psychosis: A Network Meta-Analysis

Frontiers in Psychiatry ◽

10.3389/fpsyt.2018.00187 ◽

2018 ◽

Vol 9 ◽

Cited By ~ 45

Author(s):

Cathy Davies ◽

Joaquim Radua ◽

Andrea Cipriani ◽

Daniel Stahl ◽

Umberto Provenzani ◽

...

Keyword(s):

High Risk ◽

Meta Analysis ◽

Psychotic Symptoms ◽

Clinical High Risk

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Personal Beliefs about Experiences in those at Clinical High Risk for Psychosis

Behavioural and Cognitive Psychotherapy ◽

10.1017/s1352465814000307 ◽

2014 ◽

Vol 43 (6) ◽

pp. 669-675 ◽

Cited By ~ 4

Author(s):

Jacqueline Stowkowy ◽

Diana O. Perkins ◽

Scott W. Woods ◽

Karissa Nyman ◽

Jean Addington

Keyword(s):

High Risk ◽

Negative Symptoms ◽

Intervention Strategies ◽

Psychotic Symptoms ◽

Clinical High Risk ◽

Personal Beliefs ◽

Negative Beliefs ◽

The Impact ◽

Important Objective

Background: Negative beliefs about illness in early psychosis have been shown to have an unfavourable impact on one's quality of life. A shift of focus in psychosis research has been on the detection of individuals considered to be at clinical high risk (CHR) of developing psychosis. Little is known about the impact that beliefs about psychotic like experiences or attenuated psychotic symptoms may have on CHR individuals. Aim: To explore these beliefs in a large sample of young people at CHR of developing psychosis using the Personal Beliefs about Experiences Questionnaire (PBEQ). Method: Beliefs about unusual experiences were assessed in 153 CHR individuals with the PBEQ. Prodromal symptoms (measured by the SIPS) and depression (measured by the CDSS) were also assessed. Results: In CHR individuals, holding more negative beliefs was associated with increased severity in depression and negative symptoms. Higher scores on suspiciousness were associated with increased negative beliefs, and higher levels of grandiosity were associated with decreased negative beliefs. Those who later transitioned to psychosis agreed significantly more with statements concerning control over experiences (i.e. “my experiences frighten me”, “I find it difficult to cope). Conclusions: The results suggest that targeting negative beliefs and other illness related appraisals is an important objective for intervention strategies.

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Sleep problems and attenuated psychotic symptoms in youth at clinical high-risk for psychosis

Psychiatry Research ◽

10.1016/j.psychres.2019.112492 ◽

2019 ◽

Vol 282 ◽

pp. 112492 ◽

Cited By ~ 3

Author(s):

Katrina B. Goines ◽

Allison M. LoPilato ◽

Jean Addington ◽

Carrie E. Bearden ◽

Kristin S. Cadenhead ◽

...

Keyword(s):

High Risk ◽

Sleep Problems ◽

Psychotic Symptoms ◽

Clinical High Risk

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Temporal association of stress sensitivity and symptoms in individuals at clinical high risk for psychosis

Psychological Medicine ◽

10.1017/s0033291712001262 ◽

2012 ◽

Vol 43 (2) ◽

pp. 259-268 ◽

Cited By ~ 54

Author(s):

J. E. DeVylder ◽

S. Ben-David ◽

S. A. Schobel ◽

D. Kimhy ◽

D. Malaspina ◽

...

Keyword(s):

High Risk ◽

Stress Tolerance ◽

Life Events ◽

Longitudinal Design ◽

Stress Sensitivity ◽

Psychotic Symptoms ◽

Clinical High Risk ◽

Prodromal Symptoms ◽

Wide Range ◽

Over Time

BackgroundIncreased sensitivity and exposure to stress are associated with psychotic symptoms in schizophrenia and its risk states, but little is known about the co-evolution of stress sensitivity and exposure with positive and other symptoms in a clinical high-risk (CHR) cohort.MethodA combined cross-sectional and longitudinal design was used to examine the associations over time of stress sensitivity and exposure (i.e. life events) with ‘prodromal’ symptoms in a cohort of 65 CHR patients assessed quarterly for up to 4 years, and at baseline in 24 healthy controls similar in age and gender.ResultsImpaired stress tolerance was greater in patients, in whom it was associated over time with positive and negative symptoms, in addition to depression, anxiety and poor function. By contrast, life events were comparable in patients and controls, and bore no association with symptoms. In this treated cohort, there was a trajectory of improvement in stress tolerance, symptoms and function over time.ConclusionsImpaired stress tolerance was associated with a wide range of ‘prodromal’ symptoms, consistent with it being a core feature of the psychosis risk state. Self-reported life events were not relevant as a correlate of clinical status. As in other treated CHR cohorts, most patients improved over time across symptom domains.

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